Pneumococcal pneumonia on the job: Uncovering the past story of occupational exposure to metal fumes and dust

Abstract The objectives of this study are to elucidate the early history of risk for pneumococcal pneumonia from occupational exposure to metal fumes and dusts, and to demonstrate the importance of searching older literature when performing reviews. We performed manual searching for articles in the Library of the Surgeon General's Office (the precursor to Index Medicus), in the Hathi Trust database, in PubMed, andby screening reference lists in literature appearing before the introduction of PubMed. An early body of literature, from the 1890s onward, recognized that pneumonia was linked to “Thomas slag,” a steel industry byproduct containing iron, manganese, and lime. Researchers, mainly in Germany, showed that workers in metal‐dust‐exposed occupations, especially using manganese, manifested an increased incidence of pneumococcal pneumonia. An outbreak of pneumococcal pneumonia in the 1930s implicated manganese fume in its etiology. In the immediate post‐World War II period, there was a brief flurry of interest in pneumonia from exposure to potassium permanganate that was soon dismissed as a chemical pneumonitis. After a hiatus of two decades, epidemiologic investigations drew attention to the pneumonia risks of welding and related metal fume exposure, bringing renewed interest to the forgotten role of pneumococcal pneumonia as an occupational disease. Occupational or environmental inhalation of manganese, iron, or irritants may be causally related to increased pneumococcal pneumonia risk. In particular, the risk associated with manganese seems to be overlooked in recent literature. An important conclusion is the importance of obtaining additional evidence through a deeper assessment of the literature in a broad historical context.

attention was followed by a hiatus in research. In 1994, a seminal paper brought new and sustained attention to this topic. 1 However, neither that publication nor those that came after sufficiently emphasized the earlier, rich literature on this topic. [2][3][4][5][6] The aim of this in-depth historical review is to show that occupational exposure to metals and fumes and dusts has been strongly and repeatedly linked to pneumococcal pneumonia in multiple reports.
Nonetheless this evidence has not been considered in an integrated manner, largely because each time the observation has been made, the previous biomedical literature has had to be rediscovered, leading to unnecessary fragmentation and confusing nosology.
The modern medical history of pneumonia is characterized by disease nosology that changed with the insights gained from evolving microbiologic and radiographic techniques. In 1880, Pasteur in France and Sternberg in the United States performed the first isolation of the pneumococcus. 7,8 By the middle of 1880s, it became finally clear that most acute pneumonia was bacterial and that infection with Streptococcus pneumoniae was a main cause of such bacterial pneumonia. 9 The earlier term "croupous pneumonia" for severe illness later gave way to "lobar pneumonia" when it was possible to radiographically assess patients.

| EARLY OCCUPATIONAL PNEUMONIAS
The potential role of occupational factors in acute bacterial pneumonia initially received scant consideration. Nonetheless, a relatively early paper, a 1900 review of the public health aspects of pneumonia, was published by the prominent British physician Newsholm. 10 Addressing the "influence of occupation," he called attention to the Registrar-General's data for deaths by occupation for 1890-1892 among those aged 25-65 years. Newsholm noted that the overall death rate for pneumonia was 107 per 1000 and was as low as 45 per 1000 among the clergy, whereas among iron and steel manufacturers and among coal-heavers, the rate was 248 and 249, respectively.

| Thomas slag pneumonia
Even before 1900, there was recognition that acute pneumonia might be linked to a byproduct of steel manufacturing, a now obscure material then known as "Thomas slag." In 1878, the British cousins Sidney Gilchrist Thomas and Percy Carlyle Gilchrist modified the Bessemer process for steel production, adding limestone to the process. Their patented innovation involved covering the interior area of the Bessemer converters with a mixture of magnesia, dolomite, tar, and lime. This resulted in an advantageous extraction of phosphorous, an unwanted contaminant, from the iron being converted to steel. The new process generated large amounts of alkaline slag, eponymously named Thomas slag (in German, Thomasschlacken). It soon was recognized that this otherwise worthless slag had monetary value as a fertilizer feedstock due to its high phosphorous content. To exploit this, the slag was crushed in special mills into a very fine powder, as its efficiency as a fertilizer depended on the minuteness of the powder. This process, as well as the transportation and emptying of the sacks of ground slag, generated very high levels of dust, very likely to be in the respirable range.
By the late 1880s, in Germany, France, and England, where Thomas slag processing had become a prominent industrial process, it became abundantly evident that Thomas slag workers suffered from a high prevalence of acute, frequently fatal, pneumonia. Dosenheimer 11 was the first to report the phenomenon in Germany. In Nantes, France, an epidemic of pneumonia was reported among workers processing Thomas slag: a commission concluded that dust from the milling of the slag was an important cause of the pneumonia. 12 Nothing was mentioned about microorganisms, but the commission's report initiated a debate as to whether the epidemic had been caused by contamination (contagion) from other workers. In May 1888 in Middlesbrough, Yorkshire, England, a drastic increase of deaths from a severe acute pleuro-pneumonia was reported. 13 Deaths typically occurred on the third to the fifth day of illness. The workmen themselves attributed it to inhalation of dust from a newly opened Thomas slag processing facility. An investigation initiated by the local government concluded that exposure to "slag dust" was not the primary source of illness but allowed that is might be an "assisting cause" making the exposed workers more susceptible to disease. A subsequent report from Middlesbrough concluded that the extremely fine dust created a distinct predisposition to pneumonia and that when the pneumonia did occur, the fatality rate was very high. 14 Three ensuing publications from Germany described additional outbreaks of severe croupous pneumonia with high mortality among groups of workers employed in extremely dusty Thomas slag mills. [15][16][17] The conclusion from these reports was that the dust irritated the lungs, giving pneumococci favorable conditions to grow. As importantly, the composition of the slag was characterized in two of these reports as containing phosphate, lime, silica, iron oxides, and manganese compounds. By 1895, comparative data from Germany showed that the multiyear cumulative prevalence of pneumonia was 14.4% (mortality 6.5%) among the Thomas slag millers compared with 2.0% (mortality 0.7%) among steel mill workers. 18 That study considered the lime in the slag as the irritative causal factor. By the turn of the 20th century, Thomas slag had crossed the Atlantic; a 1903 report by the United States Bureau of Labor reported that the dust arising from grinding basic Thomas slag caused severe respiratory disease. 19 Thomas slag pneumonia became a widely enough recognized phenomenon to be covered in relevant textbooks. As early as 1896, for example, a German occupational medicine specialty textbook noted that work in Thomas slag mills was associated with lethal pneumonias. 20 The stated opinion was that the alkaline lime eroded the mucous membrane of the airways and injured the deeper tissue; there was no mention of pneumococci in that text. In the first International Labour Organization Encyclopedia of 1930, the definitive indicator of widespread recognition of the phenomenon in the discipline of occupational health, an extensive chapter was dedicated to the topic, concluding that exposure to Thomas slag caused pneumococcal pneumonia. 21 Also, on the international level, at the eighth International Congress for Occupational Accidents and Occupational Medicine held in Frankfurt am Main, 1938, one of the keynote lectures acknowledged that the milling of Thomas slag increased the risk for bacterial pneumonia and that the irritating properties of the slag promoted bacterial growth. 22 In the years bridging the First World War into the Second World War, the German occupational medicine literature continued to give considerable attention to work-related pneumonia in the Thomasschlacken trade. 23,24 Underscoring this, in 1926, Thomasschlacken pneumonia was officially listed in Germany as an occupational disease. 25 Throughout the 1930s and even into the war years, German researchers continued to describe the epidemiology of very severe pneumonia, with high mortality, among workers processing Thomas slag, with exposure to manganese specifically considered as a possible etiologic factor, in addition to irritating dust. 26,27 Ultimately, German researchers could not confirm experimentally that manganese oxide, the form of manganese in Thomas slag, was the etiologic factor in Thomasschlackenpneumonie. 28 Researchers returned to the earlier view that the adverse effects of exposure to Thomas slag most likely were mediated through a local irritating effect of this very alkaline material.
But in any event, in the post-War period Thomas slag pneumonia became irrelevant, as the use of Thomas slag as fertilizer decreased sharply as chemical nitrogen, phosphorous, and potassium fertilizers came into broad use. 29 The Thomas slag industry disappeared and, in modern occupational medicine textbooks, the phenomenon of Thomas slag pneumonia is no longer mentioned at all.

| The Norwegian story
In the meantime, another form of fume-associated pneumonia had emerged, an instance in which exposure to manganese was highly suspected as an etiologic factor. In 1923, a manganese smelter was established in the Norwegian town of Sauda, located in a narrow valley in southwestern Norway. The new facility emitted large amounts of manganese-rich smoke and, as the valley was very narrow, most of the households in the village were heavily exposed to ambient pollution from this source.
In the late autumn of 1923, local physicians noted an increased occurrence of lobar pneumonia (croupous pneumonia) with all the classic clinical signs, including the abrupt onset of high fever, dyspnea, cyanosis, and radiological signs of lobar pneumonia. During the years that immediately followed, physicians in Sauda continued to note a considerably increased occurrence of fatal pneumonia in the local population. Initial investigations concluded, incorrectly, that this accumulation of lethal cases of pneumonia was not associated with the pollution from the smelter. 30 In the decade that followed, the mortality and morbidity from lobar pneumonia in Sauda continued to be high compared with the rest of Norway. In 1938, a local physician in Sauda, Dagfinn Elstad, presented a study in which he showed quite convincingly that the epidemic probably was linked to emission of manganese oxides from the smelter. 31 In that report, he presented data documenting that the mortality in pneumonia was much higher in Sauda compared with the general Norwegian population, showing that the age-adjusted mortality rate from croupous pneumonia was around 40/10,000 in Sauda compared with the national rates of 4/10,000. The ferromanganese and silicomanganese produced at the Sauda smelter contained 80%-90% manganese and 14% iron, but the ferrosilica contained only 25%-30% manganese and 60%-70% iron. Elstad's data further showed that the mortality and morbidity in Sauda from croupous (lobar) pneumonia were closely related to the production of ferromanganese: the years with high production of ferromanganese saw higher mortality as compared with lower mortality in years when the production of ferrosilica was higher. acknowledged in the international medical press and he was cited by the leading researchers in the field. 33

| Manganese or iron?
German researchers also raised the possibility that it was manganese that acted as an important factor in work-related pneumonia observed not only in Thomas mills but also in other industries. [34][35][36] This hypothesis received support from reports of occupationally associated pneumonia from other manganese exposure scenarios (Table 1). In manganese mines and manganese smelters, multiple reports described severe pneumonia in workers with heavy exposure to manganese dioxide. 23,24,36,38,39,41,42,47 In addition, harbor workers loading manganese ore were noted to have an increased incidence of pneumonia, documented in two nearly simultaneous reports half a world apart. 38,47 In another study, Baader,48 in addition to emphasizing the neurotoxicological manifestations of manganese among German battery factory workers, also noted an increased occurrence of severe pneumonias from this metal. In subsequent reviews of the topic, Büttner 49,50 described the occupational manganese exposure in Germany in 14 mines, 6 ferromanganese mills, and 55 battery factories. He concluded that manganese-exposed workers had considerably higher mortality due to pneumonia compared with other miners in the Ruhr area. As a preventive action, he argued for dust reduction in these workplaces. German researchers also visited manganese mines in Egypt, where they described a high mortality from pneumonia. 46 In this period, exposure to iron also was considered as an etiologic factor for pneumonia of potential importance. Data from a manganese mine at Giessener in the Rhineland demonstrated high mortality from croupous pneumonia compared with manual workers and iron-ore miners. 43 The mine ore contained 17% manganese but also 20% iron. The iron-ore miners without manganese co-exposure also manifested increased pneumonia mortality and the authors discussed whether iron could be a pathogenic factor, in addition to These observations, suggesting that infectious pneumonia was indeed an outcome of manganese exposure, were counterbalanced by animal experimentation data included in the same publication. The animal component of the study found that mice exposed to manganese dust from the milling room and control mice exposed to lime dust (calcium carbonate) both showed marked manganeseassociated pulmonary inflammation. Moreover, in mice further exposed to pneumococci, the mortality was similar in both the manganese-exposed and lime-dust-exposed control animals. The authors concluded that workers were at increased risk of pneumonia, but that this might be wholly an irritant phenomenon without increased susceptibility to pneumococcal infection. A follow-up study reported four additional workers suffering from pneumonia but also presented additional experimental animal data, the latter showing lung injury from intratracheal installation of manganese oxide. On balance, the authors concluded that the syndrome was a "pneumonitis,, not primary a bacterial pneumonia. 54 These two publications, both by Lloyd Davis, are particularly important in the history of occupational exposure, especially to manganese and the associated risk of pneumonia. These findings essentially reinforced previous German research showing that workers in manganese-exposed occupations had an increased occurrence of severe pneumonia. Further, also like the German studies, the potassium permanganate papers concluded that exposure to irritants were playing a mechanistic role. Nonetheless, reconceptualizing the condition as a pneumonitis rather than pneumonia downplayed an infectious etiology. A critical reassessment of the human data in these studies, however, suggests that the construct of a toxic pneumonitis applied to these observations is far from convincing, given that the reported clinical picture resembles severe infectious pneumonia, not an irritant pneumonitis. As these two studies were published in the English language at the advent of a new post-World War II period in industrial medicine, their impact likely was disproportionate to the far larger body of German language biomedical literature that preceded them.
In the decades that followed the Lloyd Davies studies, the potential link between occupational exposures and pneumococcal pneumonia was uncommonly considered, although the topic did not fall into the complete obscurity that Thomas slag pneumonia had. In the mid-1950s, for example, manganese was alluded to as a risk factor for lobar pneumonia in major English and German language textbooks of occupational medicine. 55,56 Moreover, occupational data from mines and smelters did sporadically appear. 57,58 Ultimately though, it would not be mining or smelting but another industrial process, welding, which would drive renewed interest in the potential industrial causes of pneumonia.

| WELDING
The process we recognize today as welding first emerged in 1881 The 1994 Coggon publication was followed be a series of elegant epidemiological investigations of the association between metal fume and pneumonia. These studies were included in a 2019 systematic review that carried out a pooled analysis of seven studies of pneumonia in welders or in individuals with metal fume exposure, finding that the median attributable fraction of disease linked to exposure was 52.5%. 69 Since that review, additional epidemiologic data further support the association between metal fumes and pneumococcal pneumonia. 70 Finally, and perhaps most critically, unless the historical record is given attention in the first place, the connection to past experience will never be made. This is very much in line with the clinical centrality of taking an occupational history in a patient who may have a work-related disease.
Our review shows that repeated cycles of discovery and forgetfulness characterize the topic of metal fume as an occupational and environmental etiologic factor in pneumococcal pneumonia. Indepth studies of other exposures support the view that such cycles characterize additional exposures as well, for example, the histories of manganese neurotoxicity, 60 chlorine inhalation injury, 73,74 and carbon disulfide toxicity. 75 Although this phenomenon also is likely to extend to other topics in occupational and environmental medicine, further analysis on a case-by-case basis is warranted to establish this as a generalizable pattern. To that end, we strongly would encourage other investigators to take an integrated, historically well-informed approach when considering relevant questions of occupational etiology and causation.